Precocious puberty under stressful conditions: new understanding and insights from the lessons learnt from international adoptions and the COVID-19 pandemic.

Neuro-biological variations in the timing of sexual maturation within a species are part of an evolved strategy that depend on internal and external environmental conditions. An increased incidence of central precocious puberty (CPP) has been described in both adopted and "covid-19 pandemic" children. Until recently, it was hypothesised that the triggers for CPP in internationally adopted children were likely to be better nutrition, greater environmental stability, and improved psychological wellbeing. However, following data collected during and after the coronavirus (COVID-19) global pandemic, other possibilities must be considered. In a society with high levels of child wellbeing, the threat to life presented by an unknown and potentially serious disease and the stressful environment created by lockdowns and other public health measures could trigger earlier pubertal maturation as an evolutionary response to favour early reproduction. The main driver for increased rates of precocious and rapidly progressive puberty during the pandemic could have been the environment of "fear and stress" in schools and households. In many children, CPP may have been triggered by the psychological effects of living without normal social contact, using PPE, being near adults concerned about financial and other issues and the fear of getting ill. The features and time of progression of CPP in children during the pandemic are similar to those observed in adopted children. This review considers the mechanisms regulating puberty with a focus on neurobiological and evolutionary mechanisms, and analyses precocious puberty both during the pandemic and in internationally adopted children searching for common yet unconsidered factors in an attempt to identify the factors which may have acted as triggers. In particular, we focus on stress as a potential factor in the early activation of the hypothalamic-pituitary-gonadal axis and its correlation with rapid sexual maturation.

From the Triage to the Intermediate Area: A Simple and Fast Model for COVID-19 in the Emergency Department.

INTRODUCTION: The early identification of patients with SARS-CoV-2 infection is still a real challenge for emergency departments (ED). First, we aimed to develop a score, based on the use of the lung ultrasonography (LUS), in addition to the pre-triage interview, to correctly address patients; second, we aimed to prove the usefulness of a three-path organization (COVID-19, not-COVID-19 and intermediate) compared to a two-path organization (COVID-19, non-COVID-19). METHODS: We retrospectively analysed 292 patients admitted to our ED from 10 April to 15 April 2020, with a definite diagnosis of positivity (93 COVID-19 patients) or negativity (179 not-COVID-19 patients) for SARS-COV-2 infection. Using a logistic regression, we found a set of predictors for infection selected from the pre-triage interview items and the LUS findings, which contribute with a different weight to the final score. Then, we compared the organization of two different pathways. RESULTS: The most informative factors for classifying the patient are known nasopharyngeal swab positivity, close contact with a COVID-19 patient, fever associated with respiratory symptoms, respiratory failure, anosmia or dysgeusia, and the ultrasound criteria of diffuse alveolar interstitial syndrome, absence of B-lines and presence of pleural effusion. Their sensitivity, specificity, accuracy, and AUC-ROC are, respectively, 0.83, 0.81, 0.82 and 0.81. The most significant difference between the two pathways is the percentage of not-COVID-19 patients assigned to the COVID-19 area, that is, 10.6% (19/179) in the three-path organization, and 18.9% (34/179) in the two-path organization (p = 0.037). CONCLUSIONS: Our study suggests the possibility to use a score based on the pre-triage interview and the LUS findings to correctly manage the patients admitted to the ED, and the importance of an intermediate area to limit the spread of SARS-CoV-2 in the ED and, as a consequence, in the hospital.

Sex-biased impact of endocrine disrupting chemicals on behavioral development and vulnerability to disease: Of mice and children.

Sex is a fundamental biological characteristic that influences many aspects of an organism's phenotype, including neurobiological functions and behavior as a result of species-specific evolutionary pressures. Sex differences have strong implications for vulnerability to disease and susceptibility to environmental perturbations. Endocrine disrupting chemicals (EDCs) have the potential to interfere with sex hormones functioning and influence development in a sex specific manner. Here we present an updated descriptive review of findings from animal models and human studies regarding the current evidence for altered sex-differences in behavioral development in response to early exposure to EDCs, with a focus on bisphenol A and phthalates. Overall, we show that animal and human studies have a good degree of consistency and that there is strong evidence demonstrating that EDCs exposure during critical periods of development affect sex differences in emotional and cognitive behaviors. Results are more heterogeneous when social, sexual and parental behaviors are considered. In order to pinpoint sex differences in environmentally-driven disease vulnerabilities, researchers need to consider sex-biased developmental effects of EDCs.

Proximate and ultimate causes of ritual behavior.

Ritual behaviour, intended as a specific, repetitive and rigid form of action flow, appears both in social and non-social environmental contexts, representing an ubiquitous phenomenon in animal life including human individuals and cultures. The purpose of this contribution is to investigate an evolutionary continuum in proximate and ultimate causes of ritual behavior. A phylogenetic homology in proximal mechanisms can be found, based on the repetition of genetically programmed and/or epigenetically acquired action patterns of behavior. As far as its adaptive significance, ethological comparative studies show that the tendency to ritualization is driven by the unpredictability of social or ecological environmental stimuli. In this perspective, rituals may have a "homeostatic" function over unpredictable environments, as further highlighted by psychopathological compulsions. In humans, a circular loop may have occurred among ritual practices and symbolic activity to deal with a novel culturally-mediated world. However, we suggest that the compulsion to action patterns repetition, typical of all rituals, has a genetically inborn motor foundation, thus precognitive and pre-symbolic. Rooted in such phylogenetically conserved motor structure (proximate causes), the evolution of cognitive and symbolic capacities have generated the complexity of human rituals, though maintaining the original adaptive function (ultimate causes) to cope with unpredictable environments.

Effects of Prenatal Exposure to a Low-Dose of Bisphenol A on Sex Differences in Emotional Behavior and Central Alpha2-Adrenergic Receptor Binding.

Prenatal exposure to bisphenol A (BPA) influences the development of sex differences neurologically and behaviorally across many species of vertebrates. These effects are a consequence of BPA's estrogenic activity and its ability to act as an endocrine disrupter even, at very low doses. When exposure to BPA occurs during critical periods of development, it can interfere with the normal activity of sex steroids, impacting the fate of neurons, neural connectivity and the development of brain regions sensitive to steroid activity. Among the most sensitive behavioral targets of BPA action are behaviors that are characterized by a sexual dimorphism, especially emotion and anxiety related behaviors, such as the amount of time spent investigating a novel environment, locomotive activity and arousal. Moreover, in some species of rodents, BPA exposure affected males' sexual behaviors. Interestingly, these behaviors are at least in part modulated by the catecholaminergic system, which has been reported to be a target of BPA action. In the present study we investigated the influence of prenatal exposure of mice to a very low single dose of BPA on emotional and sexual behaviors and on the density and binding characteristics of alpha2 adrenergic receptors. Alpha2 adrenergic receptors are widespread in the central nervous system and they can act as autoreceptors, inhibiting the release of noradrenaline and other neurotransmitters from presynaptic terminals. BPA exposure disrupted sex differences in behavioral responses to a novel environment, but did not affect male mice sexual behavior. Importantly, BPA exposure caused a change in the binding affinity of alpha2 adrenergic receptors in the locus coeruleus and medial preoptic area (mPOA) and it eliminated the sexual dimorphism in the density of the receptors in the mPOA.

Hormones and human developmental plasticity.

Natural selection favors the evolution of mechanisms that optimize the allocation of resources and time among competing traits. Hormones mediate developmental plasticity, the changes in the phenotype that occur during ontogeny. Despite their highly conserved functions, the flexibilities of human hormonal systems suggest a strong history of adaptation to variable environments. Physiological research on developmental plasticity has focused on the early programming effects of stress, the hypothalamus-pituitary-adrenal axis (HPAA) and the hypothalamus-pituitary-gonadal axis (HPGA) during critical periods, when the hormones produced have the strongest influence on the developing brain. Often this research emphasizes the maladaptive effects of early stressful experiences. Here we posit that the HPAA and HPAG systems in human developmental plasticity have evolved to be responsive to complex and dynamic problems associated with human sociality. The lengthy period of human offspring dependency, and its associated brain development and risks, is linked to the uniquely human combination of stable breeding bonds, extensive paternal effort in a multi-male group, extended bilateral kin recognition, grandparenting, and controlled exchange of mates among kin groups. We evaluate an evolutionary framework that integrates proximate physiological explanations with ontogeny, phylogeny, adaptive function, and comparative life history data.

Testosterone, cortisol, and status-striving personality features: A review and empirical evaluation of the Dual Hormone hypothesis.

Decades of research in behavioral endocrinology has implicated the gonadal hormone testosterone in the regulation of mating effort, often expressed in primates in the form of aggressive and/or status-striving behavior. Based on the idea that neuroendocrine axes influence each other, recent work among humans has proposed that links between testosterone and indices of status-striving are rendered conditional by the effects of glucocorticoids. The Dual Hormone hypothesis is one particular instance of this argument, predicting that cortisol blocks the effects of testosterone on dominance, aggression, and risk-taking in humans. Support for the Dual Hormone hypothesis is wide-ranging, but considerations of theoretical ambiguity, null findings, and low statistical power pose problems for interpreting the published literature. Here, we contribute to the development of the Dual Hormone hypothesis by (1) critically reviewing the extant literature-including p-curve analyses of published findings; and, (2) "opening the file drawer" and examining relationships between testosterone, cortisol, and status-striving personality features in seven previously published studies from our laboratories (total N = 718; median N per feature = 318) that examined unrelated predictions. Results from p-curve suggest that published studies have only 16% power to detect effects, while our own data show no robust interactions between testosterone and cortisol in predicting status-striving personality features. We discuss the implications of these results for the Dual Hormone hypothesis, limitations of our analyses, and the development of future research.

The Influence of Endogenous Opioids on the Relationship between Testosterone and Romantic Bonding.

The endogenous opioid system has received attention and extensive research for its effects on reward, pleasure, and pain. However, relative to other neurochemicals, such as oxytocin, vasopressin and dopamine, the function of opioids in regulating human attachment, sociosexuality, and other aspects of human sociality has not received much consideration. For example, nonapeptides (oxytocin and vasopressin) have been extensively studied in animals and humans for their possible roles in mother-offspring attachment, romantic attachment, fatherhood, and social cognition. Likewise, others have proposed models wherein oxytocin and vasopressin are moderators of the relationship between steroid hormones and human social behaviors. Recently, opioids have generated renewed interest in relation to social pain, and importantly, the brain opioid hypothesis of social attachment (BOTSA), which suggests that endogenous opioids are a key implementer in primate and human bonding, has received some support. Here we focus on romantic bonds by proposing that endogenous opioids are an important mechanism mediating reproductive trade-offs through their inhibitory effects on testosterone production.

Social network centrality and hormones: The interaction of testosterone and cortisol.

In this study we tested whether testosterone and cortisol interacted in predicting social network centrality within a male rugby team. Using social network analysis (SNA), three measures of centrality were investigated: popularity (i.e., the number of incoming ties a participant receives), gregariousness (i.e., the number of ties leaving from a participant and reaching out to others), and betweenness (i.e., the number of times a person lies between two other individuals). In line with the idea that testosterone and cortisol jointly regulate the emergence of social status, we found that individuals with high basal testosterone and low basal cortisol were more popular and more likely to act as connectors among other individuals (i.e., betweenness). The same hormonal profile was not predictive of gregariousness. However, in line with the small literature on the topic, we found that cortisol was inversely correlated with gregariousness. Despite the cross-sectional and correlational nature of our research design, these findings represent the first empirical evidence that testosterone and cortisol interact to predict complex measures of social hierarchy position derived from social network analyses.

Interest in Babies Negatively Predicts Testosterone Responses to Sexual Visual Stimuli Among Heterosexual Young Men.

Men's testosterone may be an important physiological mechanism mediating motivational and behavioral aspects of the mating/parenting trade-off not only over time but also in terms of stable differences between mating-oriented and parenting-oriented individuals. In this study, we tested the hypothesis that self-reported interest in babies is inversely related to testosterone reactivity to cues of short-term mating among heterosexual young men. Among 100 participants, interest in babies was related to a slow life-history strategy, as assessed by the Mini-K questionnaire, and negatively related to testosterone responses to an erotic video. Interest in babies was not associated with baseline testosterone levels or with testosterone reactivity to nonsexual social stimuli. These results provide the first evidence that differential testosterone reactivity to sexual stimuli may be an important aspect of individual differences in life-history strategies among human males.

Cortisol, salivary alpha-amylase and children's perceptions of their social networks.

In recent years there has been a growing interest in the use of social network analysis in biobehavioral research. Despite the well-established importance of social relationships in influencing human behavior and health, little is known about how children's perception of their immediate social relationships correlates with biological parameters of stress. In this study we explore the association between two measures of children's personal social networks, perceived network size and perceived network density, with two biomarkers of stress, cortisol and salivary alpha-amylase. Forty children (mean age = 8.30, min age = 5, and max age = 12) were interviewed to collect information about their friendships and three samples of saliva were collected. Our results show that children characterized by a lower pre-interview cortisol concentration and a lower salivary alpha-amylase reactivity to the interview reported the highest density of friendships. We discuss this result in light of the multisystem approach to the study of children's behavioral outcomes, emphasizing that future work of this kind is needed in order to understand the cognitive and biological mechanisms underlying children's and adolescents' social perceptual biases.

Eveningness is associated with higher risk-taking, independent of sex and personality.

This study tested the hypotheses that eveningness is associated with higher risk-taking propensities across different domains of risk and that this association is not the result of sex differences or confounding covariation with particular personality traits. Study participants were 172 men and women between 20 and 40 years of age. Surveys assessed chronotype, domain-specific risk-taking and risk-perception, and Big Five personality dimensions. Eveningness was associated with greater general risk-taking in the specific domains of financial, ethical, and recreational decision making. Although risk-taking was associated with both risk perception and some personality dimensions, eveningness predicted risk-taking independent of these factors. Higher risk-taking propensities among evening types may be causally or functionally linked to their propensities for sensation- and novelty-seeking, impulsivity, and sexual promiscuity.

Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A (BPA): evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation.

Exposure to bisphenol A (BPA) is implicated in many aspects of metabolic disease in humans and experimental animals. We fed pregnant CD-1 mice BPA at doses ranging from 5 to 50,000µg/kg/day, spanning 10-fold below the reference dose to 10-fold above the currently predicted no adverse effect level (NOAEL). At BPA doses below the NOAEL that resulted in average unconjugated BPA between 2 and 200pg/ml in fetal serum (AUC0-24h), we observed significant effects in adult male offspring: an age-related change in food intake, an increase in body weight and liver weight, abdominal adipocyte mass, number and volume, and in serum leptin and insulin, but a decrease in serum adiponectin and in glucose tolerance. For most of these outcomes non-monotonic dose-response relationships were observed; the highest BPA dose did not produce a significant effect for any outcome. A 0.1-µg/kg/day dose of DES resulted in some but not all low-dose BPA outcomes.

Non-monotonic dose effects of in utero exposure to di(2-ethylhexyl) phthalate (DEHP) on testicular and serum testosterone and anogenital distance in male mouse fetuses.

Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental contaminant. Epidemiological studies suggest that DEHP decreases masculinization of male fetuses. Numerous rat studies report DEHP reduces fetal testosterone production at doses greatly exceeding human exposure. We fed pregnant CD-1 mice 0.5-500,000 µg/kg/day DEHP from gestation day (GD) 9-18 and examined mothers and male fetuses on GD 18. We assessed non-monotonic dose-response by adding a quadratic term to a simple linear regression model. Except at the 500,000 µg/kg/day dose, DEHP stimulated an increase in maternal and fetal serum testosterone and increased anogenital distance (AGD). Non-monotonic dose-response curves were noted for AGD and maternal, and testis testosterone (P values 0.013-0.021). Because data from our highest dose (500,000 µg/kg/day) did not differ significantly from controls, this dose could have been incorrectly assumed to be the NOAEL had we only tested very high doses, as is typical in studies for regulatory agencies.

Hormonal mechanisms for regulation of aggression in human coalitions.

Coalitions and alliances are core aspects of human behavior. All societies recognize alliances among communities, usually based in part on kinship and marriage. Aggression between groups is ubiquitous, often deadly, fueled by revenge, and can have devastating effects on general human welfare. Given its significance, it is surprising how little we know about the neurobiological and hormonal mechanisms that underpin human coalitionary behavior. Here we first briefly review a model of human coalitionary behavior based on a process of runaway social selection. We then present several exploratory analyses of neuroendocrine responses to coalitionary social events in a rural Dominican community, with the objective of understanding differences between in-group and out-group competition in adult and adolescent males. Our analyses indicate: (1) adult and adolescent males do not elevate testosterone when they defeat their friends, but they do elevate testosterone when they defeat outsiders; (2) pre-competition testosterone and cortisol levels are negatively associated with strength of coalitionary ties; and (3) adult males usually elevate testosterone when interacting with adult women who are potential mates, but in a striking reversal, they have lower testosterone if the woman is a conjugal partner of a close friend. These naturalistic studies hint that reciprocity, dampening of aggression, and competition among friends and allies may be biologically embedded in unique ways among humans.

Evolutionary functions of early social modulation of hypothalamic-pituitary-adrenal axis development in humans.

The hypothalamic-pituitary-adrenal axis (HPAA) is highly responsive to social challenges. Because stress hormones can have negative developmental and health consequences, this presents an evolutionary paradox: Why would natural selection have favored mechanisms that elevate stress hormone levels in response to psychosocial stimuli? Here we review the hypothesis that large brains, an extended childhood and intensive family care in humans are adaptations resulting from selective forces exerted by the increasingly complex and dynamic social and cultural environment that co-evolved with these traits. Variations in the modulation of stress responses mediated by specific HPAA characteristics (e.g., baseline cortisol levels, and changes in cortisol levels in response to challenges) are viewed as phenotypically plastic, ontogenetic responses to specific environmental signals. From this perspective, we discuss relations between physiological stress responses and life history trajectories, particularly the development of social competencies. We present brief summaries of data on hormones, indicators of morbidity and social environments from our long-term, naturalistic studies in both Guatemala and Dominica. Results indicate that difficult family environments and traumatic social events are associated with temporal elevations of cortisol, suppressed reproductive functioning and elevated morbidity. The long-term effects of traumatic early experiences on cortisol profiles are complex and indicate domain-specific effects, with normal recovery from physical stressors, but some heightened response to negative-affect social challenges. We consider these results to be consistent with the hypothesis that developmental programming of the HPAA and other neuroendocrine systems associated with stress responses may facilitate cognitive targeting of salient social challenges in specific environments.

Co-ruminating increases stress hormone levels in women.

Same-sex friendships are an important source of social support and typically contribute to positive adjustment. However, there can be adjustment trade-offs if the friends co-ruminate (i.e., talk excessively about problems) in that co-rumination is related to having close friendships but also to increased internalizing symptoms. The current study utilized an experimental manipulation that elicited co-rumination in young women and thus mirrored an everyday response to stress. Observed co-rumination was associated with a significant increase in the stress hormone, cortisol (after controlling for self-reported co-rumination and for cortisol levels assessed before the discussion of problems). These findings suggest that co-rumination can amplify, rather than mitigate, the hormonal stress response to personal life stressors.